This invention relates to compounds useful as agents for the treatment of central nervous system disorders. More particularly, this invention relates to aroyl aminoacyl pyrrole compounds useful as agents for the treatment of central nervous system disorders including, but not limited to, epilepsy and neuropathic pain and methods for the treatment thereof.
The conditions grouped under the term xe2x80x9ccentral nervous system disorderxe2x80x9d constitute an area of continuing medical need. Such conditions include those disorders associated with convulsions, epilepsy, neuroprotective diseases, muscle tension and neuropathic pain.
Epilepsy continues to be an area of development for new drugs and therapies. The structures of newer anticonvulsants has been summarized in Drugs of the Future, 1991, (16) 317-320. However, the impact of such drugs and therapies have yet to be fully evaluated.
Neuropathic pain is defined as pain caused by aberrant somatosensory processing in the peripheral or central nervous system. Chronic or debilitating conditions, such as post-herpetic neuralgia and phantom limb syndrome, are categorized as neuropathic pain.
Central nervous system disorders are widespread and cause pain and suffering. Moreover, current methods of treating such disorders are often inadequate.
Anticonvulsants have been suggested for the treatment of neuropathic pain. Nadin Attal, et al., Effects of Gabapentin on the Different Components of Peripheral and Central Neuropathic Pain Syndromes: A Pilot Study, Fr. Eur. Neurol. 1998, 40(4), 191-200 describes the anticonvulsant gabapentin having the following formula: 
U.S. Pat. No. 5,760,007 describes other anticonvulsants useful in the treatment of neuropathic pain. More particularly, the reference describes the use of the anticonvulsant topiramate in treating neuropathic pain, wherein topiramate has the following general formula: 
Also, WO 98/07447 describes compositions combining an anticonvulsant and a non-toxic NMDA (N-methyl-D-aspartate) antagonist for use in neuropathic pain. Anticonvulsants suitable for use in the described combination include lamotrigine, gabapentin, valproic acid, topiramate, famotidine, phenobarbital, diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, clonazepam, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, phenytoin sodium, valproate sodium, clobazam, sulthiame, dilantin, diphenylan and L-5-hydroxytryptophan.
U.S. Pat. No. 5,332,736 to Carmosin, et al, describes other aroyl aminoacyl pyrrole compounds as useful anticonvulsants. The aroyl pyrrole compounds of the present invention, however, have not been previously described as useful agents for the treatment of central nervous system disorders.
Accordingly, it is an object of the present invention to provide aroyl pyrrole compounds useful as agents for the treatment of central nervous system disorders. It is also an object of the present invention to teach a method for the treatment of central nervous system disorders using the aroyl pyrrole compounds of the present invention including, but not limited to, their use as anticonvulsants, antiepileptics, neuroprotective agents, muscle relaxants and agents for the treatment of neuropathic pain.
The present invention provides aroyl aminoacyl pyrrole compounds as agents for the treatment of central nervous system disorders having Formula (I) and Formula (II): 
wherein
A is a substituent selected from the group consisting of aryl and heteroaryl optionally substituted with one to two substituents selected from the group consisting of halogen, C1-8alkyl, C1-8alkoxy, tri(halogen)C1-8alkyl and tri(halogen)C1-8alkoxy;
n is an integer from 1 to 5;
R1 is C1-8alkyl optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, C1-8alkoxy (optionally substituted with xe2x80x94SC1-8alkyl), C1-8acyl, carboxy, carbonyl (further substituted with C1-8alkyl, C1-8alkoxy, amino or xe2x80x94SC1-8alkyl), oxy (further substituted with carbonylC1-8alkyl, carbonylC1-8alkoxy or carbonylamino), amino (optionally further substituted with one or two substituents independently selected from C1-8alkyl, C1-8acyl, carbonylC1-8alkyl, carbonylC1-8alkoxy, sulfinylC1-8alkyl or sulfonylC1-8alkyl), ureido (optionally further substituted with C1-8alkyl), thio (optionally further substituted with C1-8alkyl or amino), sulfinyl (optionally further substituted with C1-8alkyl or amino) and sulfonyl (optionally further substituted with C1-8alkyl or amino);
R2 and R3 are substituents independently selected from the group consisting of hydrogen and C1-8alkyl;
R4 and R5 are substituents independently selected from the group consisting of hydrogen, C1-8alkyl and arylC1-8alkyl; wherein aryl is optionally substituted with one to three substituents selected from the group consisting of C1-8alkyl, C1-8alkoxy, tri(halo)C1-8alkyl and tri(halo)C1-8alkoxy;
or, in the alternative, R4 and R5 may be fused together with nitrogen to form a heterocyclic ring selected from the group consisting of: 
wherein x is an integer from 3 to 7 and Y is selected from the group consisting of N, S, Sxe2x95x90O, SO2 and 0; and
R6 is a substituent selected from the group consisting of C1-8alkyl and hydroxyC1-8alkyl;
and pharmaceutically acceptable acid addition salts thereof;
with the proviso that,
in the case of compound wherein:
wherein
n is an integer from 1 to 5; R1 is selected from the group consisting of hydrogen and C1-4alkyl; R2 and R3 are selected from the group consisting of hydrogen and C1-4alkyl; R4 and R5 are independently selected from the group consisting of hydrogen, C1-4alkyl, phenylC1-4alkyl and substituted phenylC1-4alkyl where the substituent is on phenyl and selected from the group consisting of methyl and methoxy; or in the alternative, are fused and together with the nitrogen form a heterocyclic ring selected from the group consisting of: 4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl, 1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-2-yl, 
wherein Y is S or O and x is 3 to 7; and, R6 is selected from the group consisting of methyl and hydroxymethyl; then, A cannot be substituted or unsubstituted phenyl.
The present invention also provides a method for the treatment of central nervous system disorders comprising the step of administering to a mammal suffering from such condition a therapeutically effective amount of an active compound selected from Formula (I) and Formula (II).
Relative to the above generic description, certain compounds of Formula (I) and Formula (II) are preferred. Preferred embodiments are those compounds wherein
A is a substituent selected from the group consisting of phenyl, naphthalenyl, furyl, thienyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or quinolinyl optionally mono- or di-substituted with chlorine, methyl, ethyl, methoxy, trifluoromethyl or trifluoromethoxy. More preferably, A is selected from phenyl, naphthalenyl, thienyl or pyridinyl optionally mono- or di-substituted with chlorine, methyl or methoxy.
n is an integer from 1 to 2.
R1 is C1-8alkyl optionally substituted with one to two substituents independently selected from the group consisting of C1-8alkoxy and amino; wherein amino is optionally substituted with one to two substituents independently selected from C1-8alkyl. More preferably, R1 is a substituent selected from the group consisting of methyl, ethyl, n-propyl, n-butyl and t-butyl optionally substituted with one to two substituents independently selected from the group consisting of methoxy, ethoxy, propoxy and amino; wherein amino is optionally substituted with one to two substituents independently selected from methyl, ethyl, n-propyl, n-butyl and t-butyl. Most preferably, R1 is a substituent selected from the group consisting of methyl, ethyl and n-propyl optionally substituted with one to two substituents independently selected from the group consisting of methoxy, ethoxy and amino; wherein amino is optionally substituted with one to two substituents independently selected from the group consisting of methyl and ethyl.
R2 and R3 are substituents independently selected from the group consisting of hydrogen, methyl, ethyl and propyl. More preferably, R2 and R3 are substituents independently selected from the group consisting of hydrogen and methyl.
R4 and R5 are substituents independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, n-butyl, benzyl, phenethyl and phenylpropyl; wherein phenyl is optionally substituted with one to three substituents selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl and trifluoromethoxy. More preferably, R4 and R5 are substituents independently selected from the group consisting of methyl, ethyl, propyl, benzyl, phenethyl and phenylpropyl; wherein phenyl is optionally substituted with one to three substituents selected from the group consisting of methyl, ethyl, methoxy and ethoxy. Most preferably, R4 and R5 are substituents independently selected from the group consisting of methyl, ethyl and propyl.
Alternatively, R4 and R5 may be fused together with nitrogen to form a substituent selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxidethiomorpholinyl, 1,1-dioxidethiomorpholinyl, piperazinyl and imidazolyl optionally substituted with a substituent selected from R6. More preferably, R4 and R5 may be fused together with nitrogen to form a substituent selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and imidazolyl optionally substituted with a substituent selected from R6. Most preferably, R4 and R5 may be fused together with nitrogen to form a substituent selected from the group consisting of piperidinyl, piperazinyl and imidazolyl optionally substituted with a substituent selected from R6.
R6 is a substituent selected from the group consisting of methyl, ethyl, propyl, n-butyl, hydroxymethyl, 1-hydroxyethyl and 1-hydroxypropyl. More preferably, R6 is a substituent selected from the group consisting of methyl, ethyl, hydroxymethyl and 1-hydroxyethyl. Most preferably, R6 is methyl.
Exemplifying the invention is a compound of Formula (I) and Formula (II) selected from:
Table 1 lists particular compounds of the present invention having Formula (I)
Table 2 lists particular compounds of the present invention having Formula (II)
Particularly preferred compounds having Formula (I) and Formula (II) for as anticonvulsant agents include
Particularly preferred compounds having Formula (I) and Formula (II) for use as agents for the treatment of neuropathic pain include
Particularly preferred compounds having Formula (I) and Formula (II) for use as both anticonvulsant modulators and modulators for the treatment of neuropathic pain include
The terms used in describing the invention are commonly used and known to those skilled in the art. As used herein, the following abbreviations have the indicated meanings:
Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and are illustrated more particularly in the schemes that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the art.
Instant compounds useful as agents for the treatment of central nervous system disorders may be placed into two categories, those having an aromatic ring at the 2-carbonyl position and those having an aromatic ring at the 4-carbonyl position. Both categories of compounds may be prepared by variations of what is fundamentally the same reaction scheme.
Scheme A exemplifies the preparation of compounds having an aromatic ring at the 2-position. Referring to Scheme A, in the first step a simple pyrrole Compound A1 is acylated with an appropriately substituted aroyl chloride Compound A2 to produce aroyl pyrrole Compound A3. This acylation may be carried out by simply heating the aroyl chloride and the pyrrole in an aprotic solvent followed by removing excess aroyl chloride by reaction with a dibasic amine and extraction with HCl.
The temperature of the acylation will vary depending upon the desired rate of reaction and the substituents of pyrrole Compound A1. Preferably the acylation is carried out at a temperature of from 50 to 250xc2x0 C. A suitable dibasic amine is dimethyl-3-aminopropyl amine. In the case where R1 is hydrogen the acylation, as described, may not produce desirable yields. In this case, a Vilsmeier type acylation as employed by J. White and G. McGillivrey, J. Org. Chem., Vol. 42, pp 42-48, 1977 might be expeditiously employed.
Subsequently, the aroyl pyrrole Compound A3 is acylated at the 4-position in a Friedel-Crafts reaction with the halogenated acid chloride Compound A4 to produce a 2-aroyl-4-halogenated alkanoyl pyrrole Compound A5. The Friedel-Crafts reaction is carried out by refluxing the halogenated carboxylic acid chloride Compound A4, in which X is Cl, Br or 1, with product Compound A3 in a solvent with a Friedel-Crafts reagent followed by treatment with HCl and evaporation of the solvent. Suitable Friedel-Crafts reagents include aluminum chloride, zinc chloride, BF3 or TiCl4. Suitable solvents include methylene chloride, 1,2-dichloroethane, carbon tetrachloride or chloroform. The temperature of reflux might vary between 30 and 150xc2x0 C.
To produce Compound A7, the 2-aroyl-4-halogenated alkanoyl pyrrole Compound A5 is aminated with amine Compound A6 to produce the desired 2-aroyl-4-aminoalkanoyl pyrrole Compound A7. The amination may be carried out by heating the reactants Compound A5 and Compound A6 neat or in a solvent to a temperature of from 40 to 120xc2x0 C. and preferably from 50 to 90xc2x0 C. Suitable solvents, where employed, include ethanol, 1-propanol or toluene. 
Scheme B exemplifies the preparation of compounds having an aromatic ring at the 4-position. Except for the specifics of the reactants, each step of Scheme B is analogous to the corresponding step of Scheme A with the reactions and description thereof being identical. Referring to Scheme B, in the first step a simple pyrrole Compound B1 is acylated with an appropriately substituted halogenated alkanoyl chloride Compound B2 to produce halogenated alkanoyl pyrrole Compound B3. Subsequently, alkanoyl pyrrole Compound B3 is acylated at the 4-position in a Friedel-Crafts reaction with aroyl acid chloride Compound B4 to produce 2-halogenated alkanoyl-4-aroyl pyrrole Compound B5. In the third reaction, 2-halogenated alkanoyl-4-aroyl pyrrole Compound B5 is aminated with amine Compound B6 to produce the desired 2-aminoalkanoyl-4-aroyl pyrrole Compound B7. 
Scheme C exemplifies the preparation of compounds wherein R1 is substituted with substituents other than methyl and the aromatic ring is at the 2-position. Referring to Scheme C in the first step a simple pyrrole Compound C1 is acylated with (dimethylamino)benzamide C2 to produce benzoyl pyrrole C3. This was accomplished by means of a Vilsmeyer reaction. Subsequent steps are identical to Scheme A through Compound C7. Compound C7 was alkylated with the appropriate haloalkyl Compound C8 in the presence of base to give Compound C9. 
Scheme D was identical to Scheme C with the exception of reversing the order of steps 3 and 4. 
The compounds herein readily form pharmaceutically acceptable acid addition salts. Such salts include hydrochlorides, sulfates, phosphates, methane sulfonates, fumarates, maleates, citrates, lactates, and the like. Those skilled in the art will readily recognize suitable methods for manufacture and use of the acid addition salts.
Specific compounds which are representative of this invention may be prepared as per the following examples offered by way of illustration and not by way of limitation. Also, examples specifically used to prepare intermediates for the further synthesis of compounds of the invention are designated by xe2x80x9cProcedure.xe2x80x9d No attempt has been made to optimize the yields obtained in any of the reactions. One skilled in the art would know how to increase such yields through routine variations in reaction times, temperatures, solvents and/or reagents.
N-Methylpyrrole (19.5 g, 0.24 mole) and 2-napthalenoyl chloride (50.0 g, 0.26 mole) 300 mL of dry toluene were heated under reflux overnight with a nitrogen stream bubbling through the reaction mixture. Another 10 mL of N-methylpyrrole was added to the reaction mixture and the reflux was continued for another 38 hr. 100 mL of 20% aqueous 3-(dimethylamino)propylamine was added and stirred for 30 minutes. Et2O/THF was added and the organics were separated off, washed with 1 N HCl, NaHCO3, water, brine and dried (MgSO4). The solvent was evaporated in vacuo to give 51 g (90%) of (2-naphthalenyl)(1-methyl-1H-pyrrol-2-yl)-methanone. mp 108-110xc2x0 C. CIMS m/z236 (MH+). 1H NMR (300 MHz, CDCl3) xcex4 8.35 (Ar, 1H); 8.0-7.9 (Ar, 4H); 7.6-7.5 (Ar, 2H); 6.95 (Ar, 1H); 6.8 (Ar, 1H); 6.2 (Ar, 1H); 4.1 (s, 3H).
Using the method of Procedure 1, substituting the correct acid chloride for the 2-naphthalenoyl chloride, the following compounds were prepared:
(oil) CIMS m/z 192 (MH+). 1H NMR (300 MHz, CDCl3) xcex4 7.75 (Ar, 1H); 7.6 (Ar, 1H); 7.1 (Ar, 1H); 7.0 (Ar, 1H); 6.9 (Ar, 1H); 6.2 (Ar, 1H); 4.0 (s, 3H).
(oil) CIMS m/z 226 (MH+).
A 71 g (0.44 mole) sample of aluminum chloride was added in portions over 15 minutes to 51 g (0.217 mole) of (2-naphthalenyl)(1-methyl-1H-pyrrol-2-yl)methanone in 500 mL of 1,2-dichloroethane (DCE) at 5xc2x0 C. After stirring for 15 minutes, a solution of 32 mL (0.44 mole) of chloroacetyl chloride in 50 mL 1,2-DCE was added dropwise. After stirring for 30 minutes, the ice bath was removed and stirred for 3 hr. The reaction mixture was poured into ice/3N HCl. The organics were washed with water, NaHCO3, water, brine, and dried (Na2SO4). The solvent was evaporated in vacuo and the residue recrystallized from EtOAc to give 41.2 g (61%) of 2-chloro-1-[4-(2-naphthalenoyl)-1-methyl-1H-pyrrol-2-yl]ethanone. mp 148-151xc2x0 C. CIMS m/z 312 (MH+). 1H NMR (300 MHz, CDCl3) xcex4 8.35 (s, 1H); 8.1-7.85 (Ar, 4H); 7.6 (Ar, 3H); 7.2 (Ar, 2H); 4.4 (s, 2H); 4.05 (s, 3H).
Using the method of Procedure 2, the following compounds were prepared:
mp 134-136xc2x0 C. CIMS m/z 267 (MH+). Anal calc""d for: C12H10ClNO2S: C, 53.83; H, 3.76; N, 5.23. Found: C, 53.67; H, 3.94; N, 5.19.
mp 110-112xc2x0 C. CIMS m/z 303 (MH+). 1H NMR (300 MHz, CDCl3) xcex4 8.1 (s, 1H); 7.8 (Ar, 1H); 7.5 (Ar, 1H); 7.3 (Ar, 1H); 4.9 (s, 2H); 3.9 (s, 3H).
By the method of procedure 2 using the hydrochloride salt of (2-pyridinyl)(1-methyl-1H-pyrrol-2-yl)methanone. CIMS m/z 263 (MH+).